Acute Myeloid Leukaemia, High Risk Myelodysplastic Syndrome
Conditions
Keywords
Pharmacokinetics, Dose escalation, Bayesian Optimal INterval (BoIN), Bromodomain-Containing Protein 9 (BRD9), Monotherapy
Brief summary
The purpose of the study is to assess the safety, pharmacokinetics, and preliminary efficacy of AMX-883 monotherapy in participants with acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) and in combination with anticancer agents in participants with AML.
Detailed description
This is a modular, Phase 1, open-label, multi-centre dose-escalation study investigating AMX-883 in participants with relapsed/refractory AML and high-risk MDS. The study comprises Module 1, which will evaluate AMX-883 as monotherapy and in combination with posaconazole. Module 1 consists of three parts: * Part A consists of the monotherapy dose escalation cohorts and investigation of the food-effect at selected dose(s). * Part B consists of AMX-883 in combination with posaconazole dose escalation cohorts. Other modules may be added by protocol amendment. The study aims to establish optimal dosing and preliminary efficacy data to support further clinical development of AMX-883.
Interventions
DRUGAMX-883
AMX-883 will be administered orally.
DRUGPosaconazole
Posaconazole tablets will be administered orally.
Sponsors
Amphista Therapeutics Ltd
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with relapsed or refractory AML who have failed all available standard therapies or relapsed or refractory high-risk MDS with BM blasts 10-19% * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Adequate washout from prior therapies * Adequate kidney and liver function * Female participants of childbearing potential must use highly effective contraception, and male participants must agree to use barrier contraception and avoid sperm donation for at least 120 days after last dose * If enrolled in M1B: Participant must have no documented contraindication to treatment with posaconazole before start of treatment
Exclusion criteria
* Diagnosis of acute promyelocytic leukaemia or chronic myelogenous leukaemia in blast crisis * Clinically active central nervous system (CNS) leukaemia * Receiving immunosuppressive therapy post HSCT * History of another malignancy that is active, progressing, or has required systemic treatment within the past 2 years * Presence of \>Grade 1 active graft versus host disease within 4 weeks prior to C1D1 * Significant cardiovascular disease * Family history of sudden cardiac death before 40 years of age or a family history of long QT syndrome * Clinically significant electrolyte imbalances (e.g., hypokalaemia, hypomagnesaemia, hypocalcaemia) that may contribute to QT interval prolongation * Clinically significant bradycardia (\<50 beats per minute) that is symptomatic or causes haemodynamic instability * Major surgery within 4 weeks prior to C1D1 or inadequate recovery from prior surgery * Uncontrolled intercurrent illness * Inability to fast, swallow, ingest, or absorb oral medication due to a pre-existing condition * History of interstitial lung disease or pneumonitis requiring systemic corticosteroid treatment * Requirement for medications with a known risk of Torsades de Pointes that cannot be discontinued prior to study treatment * Detectable human immunodeficiency virus (HIV) viral load * Known serologic status reflecting active hepatitis B or C infection * Active uncontrolled systemic fungal, bacterial, viral, or other infection or a condition predisposing to severe infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse events of special interests (AESIs) and serious adverse events (SAEs) | Until 30 days after last dose (Approximately 2 years 8 months) | To determine the safety and tolerability of AMX-883 in participants with relapsed or refractory AML and high-risk MDS when administered as monotherapy and in combination with posaconazole. |
| Number of participants with dose limiting toxicities (DLTs) | During Cycle 1 (each cycle will be 28 days) | To determine the maximum tolerated dose (MTD)/optimal biological dose (OBD) and the recommended dose for expansion (RDE) of AMX-883 in participants with relapsed or refractory AML and high-risk MDS when administered as monotherapy and in combination with posaconazole. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum plasma concentration (Cmax) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (Cmax) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Cmax) of AMX-883. |
| Minimum plasma concentration (Cmin) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (Cmin) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Cmin) of AMX-883. |
| Time to Cmax (Tmax) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (Tmax) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Tmax) of AMX-883. |
| Terminal plasma half-life (t½λz) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (t½λz) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (t½λz) of AMX-883. |
| Area under the plasma concentration-time curve from zero to infinity (AUCinf) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (AUCinf) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (AUCinf) of AMX-883. |
| Oral plasma clearance (CL/F) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (CL/F) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (CL/F) of AMX-883. |
| Oral volume of distribution during terminal phase (Vz/F) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (Vz/F) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (Vz/F) of AMX-883. |
| Mean residence time (MRT) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (MRT) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (MRT) of AMX-883. |
| Area under the plasma concentration-time curve from zero to tau (AUC0-tau) where tau=12 | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To characterise the PK (AUC0-tau) parameters of AMX-883 after a single dose and at steady state when administered as monotherapy and in combination with posaconazole and to characterise the effect of a high-fat meal on the PK (AUC0-tau) of AMX-883. AUC at other timepoints may also be derived. |
| Composite complete remission (CRc) (AML) | Approximately 2 years 8 months | CRc is defined as percentage of participants with Complete remission (CR) and complete remission with partial haematologic recovery (CRh) and complete remission with incomplete count recovery (CRi). This will be used to explore early evidence of antileukaemic activity (ALA) of AMX-883 when administered as monotherapy and in combination with posaconazole in participants. |
| Morphologic leukaemia-free state (MLFS) (AML) | Approximately 2 years 8 months | MLFS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Overall Response rate (ORR) (AML) | Approximately 2 years 8 months | ORR is defined as CR, CRh, or CRi with or without MRD. ORR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Duration of remission (DOR) (AML) | Approximately 2 years 8 months | DOR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Transfusion independence (TI) (AML) | Approximately 2 years 8 months | TI will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Relapse-free survival (RFS) (AML) | Approximately 2 years 8 months | RFS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Progression-free survival (PFS) (AML) | Approximately 2 years 8 months | PFS is defined as the time from the first dose until which participants can continue receiving treatment without experience any progressive disease. PFS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Event-free survival (EFS) (AML) | Approximately 2 years 8 months | EFS is defined as the failure to achieve CR. EFS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Time to response (TTR) (AML) | Approximately 2 years 8 months | TTR is defined as the time taken to achieve CR, ORR and CRc after starting the treatment. TTR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Overall survival (OS) (AML) | Approximately 2 years 8 months | OS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| Treatment failure (AML) | Approximately 2 years 8 months | Treatment failure will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| 30-day and 60-day mortality rate (Extramedullary Disease- 30 [ED-30] and ED-60) (AML) | Approximately 2 years 8 months | ED-30 and ED-60 will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with AML. |
| CR (high-risk MDS) | Approximately 2 years 8 months | CR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| CR equivalent (high-risk MDS) | Approximately 2 years 8 months | CR equivalent will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| Partial remission (PR) (high-risk MDS) | Approximately 2 years 8 months | PR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| Complete remission with limited count recovery (CRL) (high-risk MDS) | Approximately 2 years 8 months | CRL will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| CRh (high-risk MDS) | Approximately 2 years 8 months | CRh will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| Haematologic improvement (HI) (high-risk MDS) | Approximately 2 years 8 months | HI will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| ORR (high-risk MDS) | Approximately 2 years 8 months | ORR is defined by CR (or CR equivalent) + PR + CRL + CRh + HI. ORR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| DOR (high-risk MDS) | Approximately 2 years 8 months | DOR is defined as CR (or CR equivalent) + PR + CRL + CRh + HI. DOR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| TTR (high-risk MDS) | Approximately 2 years 8 months | TTR is defined as the time from first dose of study treatment to the first documented evidence of achieving a CR, ORR and CRc. TTR will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| PFS (high-risk MDS) | Approximately 2 years 8 months | PFS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| EFS (high-risk MDS) | Approximately 2 years 8 months | EFS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| OS (high-risk MDS) | Approximately 2 years 8 months | OS will be used to explore early evidence of ALA of AMX-883 when administered as monotherapy and in combination with posaconazole in participants with high-risk MDS. |
| Change from baseline in BRD9 expression levels in peripheral blood mononuclear cells (PBMCs) | At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months) | To investigate biomarkers potentially related to AMX-883 activity when administered as monotherapy and in combination with posaconazole. |
Countries
United States
Contacts
CONTACTAmphista Medical Monitor
Outcome results
None listed